4p-syndrome. This 10-year-old girl with 4p-syndrome has characteristic facies. She has profound psychomotor retardation. She does not walk or talk.
Cardiovascular :
Atrial and ventricular septal defects, pulmonary stenosis.
Neuromuscular :
Severe mental and motor delay. Hypotonia, seizures. Seizures often severe in infancy and decrease in frequency after age 5 years. May have absent septum pellucidum, agenesis of the corpus callosum, lateral and third ventricle enlargement, interventricular cysts.
Orthopedic :
Scoliosis. Simian crease, hyperconvex nails, polydactyly. Absent pubic rami, congenital hip dislocation, metatarsus adductus, clubfoot deformity. Fused or bifid vertebrae. Short stature.
GI/GU :
Malrotation of the gut. Hypospadias, cryptorchidism, absent uterus. Renal hypoplasia.
Other :
Intrauterine growth retardation. Precocious puberty. May have variable deficiency of one of several immunoglobulins.
Anesthetic Considerations
Micrognathia may make direct laryngoscopy and tracheal intubation difficult. A single case of malignant hyperthermia in a young child with Wolf-Hirschhorn syndrome has been reported (6), but there is no other evidence that malignant hyperthermia is associated with the syndrome (2,5). Chronic use of anticonvulsant medications may affect the metabolism of some anesthetic drugs. Care must be taken in positioning because of scoliosis and possible congenital hip dislocation. Patients with congenital heart disease should receive an appropriately tailored anesthetic.
Bibliography :
1. Battaglia A , Filippi T , Carey JC , et al. Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision. Am J Med Genet C 2008;148:246–251.
2. Mohiuddin S , Mayhew JF . Anesthesia for children with Wolf-Hirschhorn syndrome: a report and literature review. Paediatr Anaesth 2005;15:254–255.
3. Iacobucci T , Nani L , Picoco F , et al. Anesthesia for a child with Wolf-Hirschhorn [sic] syndrome [Letter]. Paediatr Anaesth 2004;14:969.
4. Marcelis C , Schrander-Stumpel C , Engelen J , et al. Wolf-Hirschhorn (4p-) syndrome in adults. Genet Couns 2001;12:35–48.
5. Sammartino M , Crea MA , Sbarra GM , et al. Absence of malignant hyperthermia in an infant with Wolf-Hirschhorn syndrome undergoing anesthesia for ophthalmologic surgery. J Pediatr Ophthalmol Strabismus 1999;36:42–43.
6. Ginsburg R , Purcell-Jones G . Malignant hyperthermia in the Wolf-Hirschhorn syndrome. Anaesthesia 1988;43:386–388.
5α-Reductase deficiency
Synonym
Pseudovaginal perineoscrotal hypospadias; Steroid 5α-reductase 2 deficiency; Pseudohermaphroditism, male
MIM #: 264600
This male-limited autosomal recessive disease is another cause of male pseudohermaphroditism. A mutation in the steroid 5α-reductase 2 gene results in defective conversion of testosterone to dihydrotestosterone. Thus, levels of testosterone are normal. At least 45 distinct mutations have been described. Masculinization at puberty is due to retained activity of the 5α-reductase 1 gene.
GI/GU :
Ambiguous genitalia. Small phallus, a bifid scrotum, and perineal hypospadias. Histologically normal testes, epididymides, and vasa deferentia. Underdeveloped seminal vesicles that lead into a vagina, which usually ends blindly. Absent or rudimentary prostate. Can have a urogenital sinus. Sperm production is minimal or absent, and fertility usually requires in vitro intervention.
Other :
With puberty, there is masculinization with deepening voice, phallic enlargement, and a scanty beard. Affected 46, XY males raised as females often revert to male gender identity at the time of expected puberty.
Miscellaneous :
Inhibition of 5α-reductase has been suggested for the prevention of male pattern baldness and for the treatment of resistant acne, benign prostatic hypertrophy, and idiopathic hirsutism. Middlesex, by Jeffrey Eugenides, the winner of the 2003 Pulitzer Prize for fiction, is told from the perspective of the protagonist, who had 5α-reductase deficiency. In a New Guinea population, the disorder is common enough that affected individuals are recognized early and assigned to a third sex. However, they face the same problems when forced to adjust to adult gender roles.
Anesthetic Considerations
A certain degree of sensitivity is required when speaking with patients, or families of patients, with intersex disorders.
Figure
See Appendix A
Bibliography :
1. Sultan C , Lumbroso S , Paris F , et al. Disorders of androgen action. Semin Reprod Med 2002;20:217–228.
2. Hochberg Z , Chayen R , Reiss N , et al. Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5-alpha-reductase 2 deficiency. J Clin Endocrinol Metab 1996;81:2821–2827.
3. Wilson JD , Griffin JE , Russel DW . Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 1993;14:577–593.
5p-Syndrome
See Cri-du-chat syndrome
5,10-Methylene tetrahydrofolate reductase deficiency
Synonym
MTHFR deficiency; Methylene tetrahydrofolate reductase deficiency
MIM #: 236250
This autosomal recessive disorder is due to a defect in 5,10-methylene tetrahydrofolate reductase (MTHFR) and leads to increased homocysteine levels. MTHFR is a cytoplasmic enzyme involved in the metabolism of the sulfur-containing amino acids. Specifically, it catalyzes the conversion of 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate. The methyl group is donated to homocysteine (catalyzed by methionine synthase) to form methionine. The clinical severity mirrors the degree of enzyme activity deficiency and the age of onset varies from infancy to adulthood. Two-thirds of patients are female. The disease can have findings similar to homocystinuria, and defects in this enzyme are referred to as homocystinuria type III. The disease is generally very difficult to treat. Certain specific mutations can be a risk factor for spina bifida and anencephaly. The C667T single nucleotide polymorphism (SNP) (the thermolabile variant) is relatively common and associated with a hypercoagulable state. It has also been associated with preeclampsia. Most patients are heterozygous for several substitutions in the gene (compound heterozygotes).
HEENT/Airway :
Microcephaly. Lens dislocation.
Cardiovascular :
High levels of homocysteine have been implicated as a cardiovascular risk factor due to increased thrombogenesis. MTHFR deficiency may be implicated in the development of coronary artery disease. The C667T SNP, which is relatively common in the population, has been shown to be associated with increased risk of asymptomatic carotid artery disease in postmenopausal women.
Neuromuscular :
Mild developmental delay and intellectual disability. Hallucinations, delusions, catatonia. Waddling gate, seizures. Proximal muscle weakness. The neuropathologic findings include dilated ventricles, microgyria, demyelination, macrophage infiltration, and gliosis. Arterial and venous cerebrovascular thrombosis can be fatal. Risk of spina bifida and anencephaly. There is variability in the age of onset of symptoms and the severity of symptoms.
Other :
Vascular thrombosis and vascular changes similar to those of homocystinuria (see later). The prothrombotic state can result in both arterial and venous thromboses. Patients have elevated homocysteine levels and homocystinuria, although to a far lesser degree than in the disease homocystinuria. A megaloblastic anemia only rarely develops in these patients. This defect may predispose to preeclampsia.
Miscellaneous :
The increased risk of spina bifida and anencephaly with certain mutations may account, at least in part, for the effect of maternal dietary folate supplementation in decreasing the risk of these defects in fetuses of normal women. Because arsenic is detoxified by demethylation, the decreased availability of methyl donors in this disease has been suggested to increase the neurotoxicity of arsenic.
Anesthetic Considerations
5,10-Methylene tetrahydrofolate reductase immediately precedes methionine synthetase in the pathway involved with methionine synthesis. Given the inhibitory effect of nitrous oxide on the latter enzyme (via irreversible oxidation of the cobalt atom of vitamin B12), nitrous oxide is usually avoided in these patients, and neurologic deterioration (6) as well as death have been reported after anesthesia with nitrous oxide (7). However, in a recent prospective study, 98 patients homozygous for an MTHFR gene variant received nitrous oxide intraoperatively without an increase in perioperative morbidity or mortality (1). These patients may be at increased risk for perioperative vascular thrombosis/embolization and merit meticulous attention to hydration and homeostasis. Patients may be on anticoagulants and require perioperative conversion to heparin. Patients should be monitored postoperatively for pulmonary emboli and myocardial infarction, although the most recent study did not show any increase in postoperative cardiac injury in patients with MHTFR (1).
Bibliography :
1. Nagele P , Brown F , Francis A , et al. Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events. Anesthesiology 2013;119:19–28.
2. Nagele P , Zeugswetter B , Wiener C , et al. Influence of methylenetetrahydrofolate reductase gene polymorphisms on homocysteine concentrations after nitrous oxide anesthesia. Anesthesiology 2008;109:36–43.
3. Baum VC . When nitrous oxide is no laughing matter: nitrous oxide and pediatric anesthesia. Paediatr Anaesth 2007;17:824–830.
4. Shay H , Frumento RJ , Bastien A . General anesthesia and methylenetetrahydrofolate reductase deficiency. J Anesth 2007;21:493–496.
5. Gerges FJ , Dalal AR , Robelen GT , et al. Anesthesia for cesarean section in a patient with placenta previa and methylenetetrahydrofolate reductase deficiency. J Clin Anesth 2006;18:455–459.
6. Lacassie HJ , Nazar C , Yonish B , et al. Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10- methylenetetrahydrofolate reductase. Br J Anaesth 2006;96:222–225.
7. Selzer RR , Rosenblatt DS , Laxova R , et al. Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 2003;349:49–50.
9p-Syndrome
MIM #: 158170
This syndrome is due to a deletion of the short arm of chromosome 9. The clinical picture is variable, but craniosynostosis, a long philtrum, hernias, and digital abnormalities are always present.
HEENT/Airway :
Craniosynostosis (particularly of metopic suture), flat occiput. Trigonocephaly. Upward-slanting palpebral fissures, epicanthal folds, prominent eyes due to hypoplastic supraorbital ridges, highly arched eyebrows. Poorly formed, posteriorly rotated ears with adherent earlobes. Midface hypoplasia with short nose, flat nasal bridge, and anteverted nostrils. Choanal atresia. Long philtrum, small mouth, cleft palate, high-arched palate. Micrognathia. Short, broad neck with low posterior hairline.
Chest :
Diaphragmatic hernia.
Cardiovascular :
Congenital cardiac defects, most frequently ventricular septal defect, patent ductus arteriosus, or pulmonic stenosis.
Neuromuscular :
Moderate to severe intellectual disability, but often with good social adaptation, and psychological similarities to those of Williams syndrome (see later) have been noted. Poor memory, visual-motor skills, and visual-spatial skills.
Orthopedic :
Normal growth, scoliosis. Long middle phalanges, short distal phalanges, simian crease, postaxial polydactyly. Foot positioning defects. Long fingers and toes.
GI/GU :
Diastasis recti, inguinal and umbilical hernias. Micropenis, cryptorchidism, hypoplastic labia majora. Hydronephrosis.
Other :
Nonketotic hyperglycinemia (see later) has been observed in a patient with 9p-syndrome, suggesting at least one of the genes for that syndrome resides on the short arm of chromosome 9.
Miscellaneous :
Acute leukemia has been associated with partial deletion of the short arm of chromosome 9, and the affected gene is usually maternally derived. 9p deletion has also been implicated in the development of other cancers.
Anesthetic Considerations
The small mouth, micrognathia, and short neck may make direct laryngoscopy and tracheal intubation difficult (1). Choanal atresia precludes placement of a nasal airway, nasal intubation, or placement of a nasogastric tube. Consider preoperative evaluation of renal function in patients with a history of renal abnormalities that predispose to renal insufficiency. Patients with congenital heart disease should receive an appropriately tailored anesthetic.
Bibliography :
1. Cakmakkaya OS , Bakan M , Altintas F , et al. Anesthetic management in a child with deletion 9p syndrome [Letter]. Paediatr Anaesth 2007;17:88–89.
2. Swinkels ME , Simons A , Smeets DF , et al. Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: delineation of the critical region for a consensus phenotype. Am J Med Genet A 2008;146:1430–1438.
10 qter Deletion syndrome
MIM #: 609625
This syndrome involves a deletion of the terminal portion of the long arm of chromosome 10. Patients have characteristic facies, variable intellectual disability, and cardiac and anogenital anomalies. Most patients have been female.
HEENT/Airway :
Microcephaly. Facial asymmetry. Upward-slanting palpebral fissures, hypertelorism. Broad, beaklike nose. Micrognathia. Short neck.
Cardiovascular :
Congenital cardiac defects of a wide variety of types.
Neuromuscular :
Variable intellectual disability.
Orthopedic :
Growth retardation. May have digital abnormalities.
GI/GU :
Can have bladder obstruction and urethral reflux and secondary urinary tract infections. Anogenital anomalies.
Anesthetic Considerations
Micrognathia and short neck may make laryngoscopy and tracheal intubation difficult. Patients with congenital heart disease should receive an appropriately tailored anesthetic.
Bibliography :
1. Yatsenko SA , Kruer MC , Bader PI , et al. Identification of critical regions for clinical features of distal 10q deletion syndrome. Clin Genet 2009;76:54–62.
2. Irving M , Hanson H , Turnpenny P , et al. Deletion of the distal long arm of chromosome 10; is there a characteristic phenotype? A report of 15 de novo and familial cases. Am J Med Genet A 2003;123:153–163.
3. Davis ST , Ducey JP , Fincher CW , et al. The anesthetic management of a patient with chromosome 10qter deletion syndrome. J Clin Anesth 1994;6:512–514.
11β-Hydroxylase deficiency
Included in Congenital adrenal hyperplasia
11β-Hydroxysteroid dehydrogenase deficiency
Synonym
11β-ketoreductase deficiency; Apparent mineralocorticoid excess
MIM #: 218030
This autosomal recessive defect in 11β-hydroxysteroid dehydrogenase results in low renin hypertension, metabolic alkalosis, and hypokalemia. This enzyme has two functional isoforms, one of which catalyzes the conversion of cortisol to cortisone (dehydrogenase activity) and the conversion of cortisone to cortisol (oxoreductase activity). The other isoform catalyzes just the conversion of cortisol to cortisone. In this disease, there is decreased conversion of cortisol to cortisone. Other features of the defect suggest a primary mineralocorticoid excess, which cannot be documented, and the defect is also known as the syndrome of apparent mineralocorticoid excess (AME) because of a defect in the first isoform type. Apparently, the defect prevents cortisol from acting as a ligand for the mineralocorticoid receptor. Symptoms can be partially or fully reversed with spironolactone.
HEENT/Airway :
Hypertensive retinopathy.
Cardiovascular :
Low renin hypertension. Left ventricular hypertrophy from systemic hypertension.
Other :
Hypokalemia. Low aldosterone levels.
Miscellaneous :
Inhibition of this enzyme may be the mechanism of licorice-induced hypertension (very uncommon in the United States, where almost all domestic licorice is artificially flavored) (2). Similar inhibition can be caused by compounds in grapefruit juice. Activity of this enzyme may be related to the development of the metabolic syndrome, obesity, and type 2 diabetes.
Anesthetic Considerations
Patients may have significant hypertension with end-organ involvement. Blood pressure must be controlled before elective surgery. Serum potassium level should be determined preoperatively. Steroid replacement therapy should be continued perioperatively.
Figure
See Appendix A
Bibliography :
1. Ferrari P . The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochem Biophys Acta 2010;1802: 1178–1187.
2. Stewart PM , Wallace AM , Valentino R , et al. Mineralocorticoid activity of licorice: 11-beta-hydroxysteroid dehydrogenase comes of age. Lancet 1987;2:821–824.
11β-Ketoreductase deficiency
See 11β-hydroxysteroid dehydrogenase deficiency
11q-Syndrome
Synonym
Jacobsen syndrome
MIM #: 147791
This syndrome is due to deletion of the terminal band of the long arm of chromosome 11. This fragment of the chromosome is known to contain a heritable folate-sensitive fragile site. Two-thirds of affected children are girls. The syndrome is characterized by intrauterine and postnatal growth retardation, trigonocephaly, carp-shaped mouth, and intellectual disability.
HEENT/Airway :
Trigonocephaly (see C syndrome for illustration). Microcephaly; less commonly macrocephaly. Epicanthal folds, telecanthus, hypertelorism, ptosis, strabismus, coloboma of iris or retina, retinal dysplasia. Low-set or malformed ears. Flat nasal bridge, short nose with upturned tip. Carp-shaped mouth. Micrognathia. Short neck.
Chest :
Frequent respiratory infections. Pectus excavatum. Missing ribs.
11q-syndrome. This 8-year-old girl with 11q-syndrome has thrombocytopenia as well as a chronic low white blood cell count. She has dysmorphic facies, mild intellectual disability, and congenital heart disease (parachute mitral valve and bicuspid aortic valve). She also has decreased pain sensation.
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